A cohort of 94,000 survivors of the Hiroshima and Nagasaki atomic bombings is being studied in collaboration with the Radiation Effects Research Foundation (RERF). Cohort studies are used to quantify radiation dose response and its dependence on histological subtype of tumor, age at exposure, sex, age at observation, and time following exposure. Among several new findings is the excess risk of basal cell, but not squamous cell carcinoma of the skin associated with radiation exposure. The radiation related risk was markedly increased as age at exposure decreased. No evidence was found for an interaction with ultraviolet radiation.There is suggestive evidence for excess risks of melanoma and Bowen's disease of the skin. A radiation related excess risk was also found for tumors of the nervous system and the risk was especially high for Schwannoma. Also, liver cancer risk was found to be strongly related to radiation dose, and there was some evidence of synergy between radiation and hepatitis C viral infection as liver cancer risk factors. A study of Salivary gland tumors found a marked excess of radiation-related tumors, largely limited to mucoepidermoid carcinoma and Warthin's tumor. Case ascertainment has been completed in studies of tumors of the breast, thyroid, and ovary, and manuscripts are in preparation. Relative to age-specific baseline rates, the radiation-related excess risk of breast cancer following exposure at young ages (<20) was considerably higher for diagnosis before age 35 than later; however, it has remained flat thereafter, showing no sign of decline over the interval 35-65 years of age. Furthermore, in modeling the excess relative risk per unit dose as a function of age at exposure, women who were exposed before age 20 have the highest risk; and women who were exposed at 40 years of age or older have the least risk. There is no indication that exposure around the ages of menarche or breast budding carries more risk than exposure during early childhood or late adolescence. Case ascertainment is also in progress for lung and lymphoid cancers. A significantly increased breast cancer risk was associated with level of unbound estradiol determined from stored serum obtained from women who later developed breast cancer and from similar controls. These data were included in a combined analysis of comparable data from several other studies, which confirmed the main result and also found a protective effect of sex hormone binding globulin. A research protocol has been submitted for a new, expanded A-bomb survivor study with twice as many breast cancer cases, utilizing more recent stored serum samples and measurement of additional hormones. A new, very large record-based study of breast cancer has been initiated to verify and refine earlier findings of interactions between reproductive history and radiation dose. A case-case approach is being used to study genetic susceptibility to radiation-related breast and ovarian cancer. The previously reported phenomenon of extremely high, dose-specific relative risks for early-onset breast cancer (before age 35) is suggestive of increased sensitivity to radiation among a genetically predisposed population subgroup, and an interesting subject for further investigation. A research protocol has been approved and archival tissues are being collected for a collaborative study, with the RERF Dept. of Radiobiology, of molecular alterations in early-onset breast and ovarian cancers among A-bomb survivors.